Treatment of migraines

ABSTRACT

Provided herein are prostaglandin F 2α  analog compositions and methods for treating migraines.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. § 120 to U.S. Application, U.S. Ser. No. 15/110,295, filed Jul.7, 2016, which is the National Stage of International Patent ApplicationSerial No. PCT/US2015/010771, filed Jan. 9, 2015, which claims thebenefit of the filing date of U.S. Provisional Application No.61/925,676, filed Jan. 10, 2014, the entire contents of which areincorporated by reference herein.

BACKGROUND

Migraine is a type of headache, which is a severe, seriouslydebilitating and usually unilateral form of episodic headache that maybe preceded by aura and that is frequently associated with bothneurological and gastrointestinal symptoms such as nausea, vomiting,diarrhea, sensitivity to light (photophobia), sound (phonophobia), andsmells (osmophobia); sleep disruption, and depression. When untreated, amigraine headache attack may last anywhere from four to 72 hours.Migraines include cluster headaches and vascular headaches and aresometimes termed sick headaches or histamine headaches.

Migraine can be divided into two major subtypes: migraine without auraand migraine with aura. Migraine without aura (MO) is a clinicalsyndrome characterized by headache attacks lasting 4-72 hours. Typicalcharacteristics of the headache are unilateral location, pulsatingquality (throbbing), moderate or severe intensity, aggravation byphysical activity (which causes a mechanical strain on meningeal bloodvessels) and association with nausea, vomiting, photophobia and/orphonophobia. About 70% of subjects suffering from migraines havemigraine without aura. In migraine with aura (MA), attacks areaccompanied by reversible focal neurological symptoms (mostly visual,but also sensory or motor symptoms). Aura develops over 5-20 minutes andlasts for less than 60 minutes. Headache with the features of MO usuallyfollows the aura. About 30% of subjects suffering from migraines havemigraine with aura.

Other, less common, types of migraine exist and include migraine withprolonged aura (aura symptoms last longer than 60 minutes); migraineaura without headache; migraine with acute onset aura; basilar migrainewhich can be associated with vertigo, gait perturbances and/or loss ofconsciousness; ophthalmoplegic migraine associated with ocularparalysis, diplopia and/or ptosis; retinal migraine; and familialhemiplegic migraine associated with hemiparesis or hemiplegia.

Pharmacological interventions for the management of migraine can becategorized into two general strategies: prevention of pain and/orassociated symptomology and treatment to relieve/stop the pain andassociated symptomology. It is commonly held that prostaglandin activityis associated with migraine and that blocking the activity ofprostaglandins is an effective treatment for migraines.

SUMMARY OF THE INVENTION

It has been discovered, unexpectedly, that topical treatment withprostaglandins reduces the frequency, severity and duration ofmigraines. Without wishing to be bound by any particular theory of theinvention, it is believed that migraines are successfully treated withprostaglandins due to the low systemic levels of prostaglandin resultingfrom topical treatment.

According to aspects of the invention, a method of treating migraine isprovided. The method involves administering topically to a subject inneed thereof a composition including a prostaglandin F_(2α) analog orpharmaceutically acceptable salt thereof, in an amount effective totreat migraine. The treatment may be administered prophylactically ortherapeutically. Topical administration is to the epidermis,conjunctival surface or other mucous membranes, typically to a nail, theskin, the hair, the surface of the eye or the inner surface of theeyelid, and the like. It also may be application or delivery to mucosalsurfaces, such as buccal, rectal and pulmonary tissue, including, forexample, by sublingual, suppository or inhaled delivery. In any of theforegoing embodiments, the prostaglandin F_(2α) analog can belatanoprost, isopropyl unoprostone, bimatoprost, travoprost, ortafluprost; or pharmaceutically acceptable salt thereof. In someembodiments, the prostaglandin F_(2α) analog or pharmaceuticallyacceptable salt thereof is bimatoprost or a pharmaceutically-acceptablesalt thereof.

It also is contemplated that the formulation be delivered other thantopically, but in amounts that will achieve the doses appropriate forthe practice of the invention. Such delivery includes oral and sustainedrelease formats.

In any of the foregoing embodiments, the prostaglandin F_(2α) analog orpharmaceutically acceptable salt thereof may be administered inconjunction with a migraine drug that is not a prostaglandin F_(2α)analog or pharmaceutically acceptable salt thereof. The administrationmay be at the same time (in the same or different formation and mode ofadministration) or in a scheme involving administration at separatetimes and by the same or separate routes of administration. In oneembodiment, the prostaglandin F_(2α) analog or pharmaceuticallyacceptable salt thereof is administered prophylactically and the otherdrug is administered acutely, i.e., abortively. According to one aspectof the invention, a topical pharmaceutical composition is providedcomprising a prostaglandin F_(2α) analog or pharmaceutically acceptablesalt thereof and a migraine drug that is not a prostaglandin F_(2α)analog. The migraine drug that is not a prostaglandin F_(2α) analog maybe any of the migraine drugs listed below. According to another aspectof the invention, a kit is provided including a topical pharmaceuticalcomposition comprising a prostaglandin F_(2α) analog or pharmaceuticallyacceptable salt thereof and a non-topical dosage form of a migraine drugthat is not a prostaglandin F_(2α) analog, such as, for example, an oraldosage form. The migraine drug that is not a prostaglandin F_(2α) analogmay be any of the migraine drugs listed below.

These and other aspects of the invention are described below in greatdetail.

DETAILED DESCRIPTION

The invention involves, in some aspects, topically administering to asubject in need thereof a composition including a prostaglandin F_(2α)analog or pharmaceutically acceptable salt thereof, in an amounteffective to treat migraine. Subjects as used herein means humansubjects. A subject in need thereof is a subject with a history ofmigraines or pre-migraine symptoms. A subject in need thereof also canbe a subject suffering from a migraine.

Administering topically means administering to the epidermis such as tothe skin, the hair, the nails, or to a mucous membrane such as thesurface of the eye, the conjunctiva, the rectum, the nose, throat orlungs, or a buccal cavity.

Prostaglandin F_(2α) analogs, as used herein, means prostaglandin F_(2α)analogs and prostamide F_(2α) analogs. Prostaglandin F_(2α) analogs areligands for and bind to the prostaglandin F_(2α) receptor and/orprostamide F_(2α) receptors. ProstaglandinF_(2α)(PGF_(2α)-Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxyoct-1-enyl)cyclopentyl)hept-5-enoicacid)) has the structure:

In some embodiments, a prostaglandin F_(2α) analog comprises twohydroxyl groups in cis configuration relative to the cyclopentane ring,and two side chains in a trans configuration relative to each other. Thenumber of double bonds in the side chains and the substituents along theside chains as well as the length of the side chains may vary, dependingon the analog. Examples of prostaglandin F_(2α) analogs include, but arenot limited to, latanoprost, isopropyl unoprostone, bimatoprost,travoprost, and tafluprost. In some embodiments, the prostaglandinF_(2α) analog is bimatoprost. In some embodiments, the prostaglandinF_(2α) analog is bimatoprost, travoprost, or latanoprost. Severalprostaglandin F_(2α) analogs are produced and available commercially, e.g., LUMIGAN® and LATISSE® (Allergan), XALATAN® (Pfizer), TRAVATAN® andTRAVATAN Z® (Alcon), TRAVO-Z™ (Micro Labs), RESCULA® (CIBA Vision),TAFLOTAN® (Santen Pharmaceutical Co.), and ZIOPTAN™ (Merck). Other formsof prostaglandin F_(2α) analogs are also contemplated, e.g., derivatives(including prodrugs) such as amides, lactones, ketones, acids,nitroderivatives, and esters of prostaglandin F_(2α) analogs (see, e.g.European Patent EP1501530 B1), as well as pharmaceutically acceptablesalts of such analogs and derivatives. Examples of such other formsinclude, but are not limited to, 15-keto-latanoprost,15-keto-bimatoprost, latanoprost nitroxide unoprostone, latanoprost freeacid, travoprost free acid, fluprostenol free acid, tafluprost freeacid, and bimatoprost free acid.

The above compounds and related prostaglandin F_(2α) analog compounds aswell as synthesis thereof are well-known in the art and have beendisclosed, e. g., in U.S. Pat. Nos. 5,296,504, 5,607,978, 5,665,773,6,011,062, 6,689,901, 6,927,300, 7,166,730, 7,157,590, 7,109,371,7,351,404, 7,388,029, 7,629,345, 7,674,921, 7,947,740, 8,227,514,8,263,054 and U.S. Publication Nos. 2012/0270946, 2012/0016136A1,2010/0105771, 2010/0010239, and 2011/0152264A1 (all of which areincorporated herein by reference).

A pharmaceutically acceptable salt is a salt that retains the desiredbiological activity of the parent compound and does not impart anyunacceptable toxicological effects (see e.g., Berge, S. M., et al.,1977, J. Pharm. Sci. 66:1-19). Examples of such salts include acidaddition salts and base addition salts. Acid addition salts includethose derived from nontoxic inorganic acids, such as hydrochloric,nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, andthe like, as well as from nontoxic organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids,and the like. Base addition salts include those derived from alkalineearth metals, such as sodium, potassium, magnesium, calcium, and thelike, as well as from nontoxic organic amines, such asN,N′-dibenzylethylenediamine, Nmethylglucamine, chloroprocaine, choline,diethanolamine, ethylenediamine, procaine, and the like.

Migraine treatments are classified as prophylactic treatments or astherapeutic treatments. Each class of treatments is administered to themigraine sufferer based on the frequency and severity of the headacheand its associated symptoms. For frequent migraines, prophylactictreatments are employed to reduce the frequency of migraines and also toreduce the severity and duration of migraines and their associatedsymptoms when they occur. For occasional migraines, therapeutictreatments are used to eliminate or reduce the severity and duration ofthe migraine and its associated symptoms after the migraine has begun.

Dosage regimens are adjusted to provide the optimum desired response.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontains a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms canbe dictated by and directly dependent on (a) the unique characteristicsof the active compound and the particular therapeutic effect to beachieved, and (b) the sensitivity in individuals to the active compound.

The pharmaceutical compositions disclosed herein may include atherapeutically effective amount of a prostaglandin F_(2α) analogdisclosed herein. A “therapeutically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result (e.g., to reduce the frequency ofmigraines and/or reduce the severity and duration of migraines and theirassociated symptoms). The effective amount of the active compounds maybe determined by one of ordinary skill in the art but will varydepending on the compound employed, the frequency of application and thedesired result. The effective amount of the composition may also varyaccording to factors such as the disease state, age, sex, and weight ofthe subject.

Typically, the dose to be administered will generally range from about0.000001 to about 50% by weight of the composition, preferably fromabout 0.001 to about 50% by weight of the composition, and morepreferably from about 0.1 to about 30% by weight of the composition.Dosage values may vary with the type and severity of the condition to bealleviated or treated. For a particular subject, specific dosageregimens can be adjusted over time according to the individual need andthe professional judgment of the person administering or supervising theadministration of the compositions.

According to certain aspects of the invention, the dosage form is atopical formulation containing a particular prostaglandin F_(2α) analog.Suitable compositions for topical administration include drops,solutions, powders, ointments, creams, lotions, pastes, gels, foams,viscous liquids, semisolids, lacquers/polishes (e.g., pigmented ornon-pigmented nail polish or lacquer), suspensions, emulsions,microemulsions, reverse emulsions, colloids, dispersions, etc., whichreleases the prostaglandin F_(2α) analog or salt thereof, alone ortogether with one or more other drugs, at a predetermined rate over adefined period of time to a defined site of application. The system ofadministration may include an applicator system or a transdermaldelivery system such as a drug-containing device (including e.g., patch,disc, etc.) which releases one or more drugs at a predetermined rate,the types of which are well known in the art. In some embodiments,topical administration involves applying a prostaglandin F_(2α) analogto the skin. The area of the skin may be an area normally experiencinghair growth or an area that does not normally experience hair growth,e.g. the dorsal tip of a phalanx (finger or toe) of a subject. In someembodiments, compositions of the invention are applied topically to atleast one nail of the subject. In some embodiments, compositions of theinvention are applied topically to at least two nails (e.g., two, three,four or five nails) of the subject. The compositions may be applied tothe whole nail, or at least one part of the nail, e.g., the cuticle,nail matrix, or the tip or end of the nail plate. The compositions mayalso be applied to the skin surrounding to the nail. The prostaglandinF_(2α) analog also may be applied to an ocular surface or to anothermucosal surface.

Topical formulations may be prepared directly, or by combining aprostaglandin F_(2α) analog-containing concentrate with a diluent, forexample, an aqueous diluent. Such topical formulations may includeadditional excipients as necessary, for example, to modify consistencyof the rate of absorption of the prostaglandin F_(2α) analog component.Specific examples of pharmaceutically acceptable excipients useful fortopical administration include olive oil, arachis oil, castor oil,mineral oil, petroleum jelly, dimethyl sulphoxide, chremophor, Miglyol182 (commercially available from Dynamit Nobel Kay-Fries ChemicalCompany, Mont Vale, N.J.), an alcohol (e.g. ethanol, n-propyl alcohol,or iso-propyl alcohol), liposomes or liposome-like products or asilicone fluid. Preferred excipients are dimethyl sulphoxide and oliveoil. Mixtures of at least two of any suitable excipients may be used.

In some embodiments, compositions of the invention are formulated as apolish or lacquer, e.g., a nail polish, for administration to the nailor at least one part of the nail. Polishes and lacquers for drugdelivery are known in the art (see, e. g., WO 9949835, U.S. PatentPublications US 2003049307, US 2003232070, U.S. Pat. Nos. 6,224,887, and5,264,206, and 5,346,692, all of which are incorporated herein byreference). Such formulations include, e.g., one or more solvents andone or more film-forming polymers. Suitable solvents include, but arenot limited to, hydrocarbons, halogenated hydrocarbons, alcohols,ethers, ketones and esters customary in cosmetics, especially acetic andesters of monohydric alcohols (ethyl acetate, n-butyl acetate etc.). Insome embodiments, the solvents can be mixed with aromatic hydrocarbonssuch as toluene and/or alcohols such as ethanol or isopropanol and/oraliphatic sulfoxides and sulfones such as, for example, dimethylsulfoxide or sulfolane. In some embodiments, the film-forming polymer isinsoluble in water. Such film-forming polymers include, but are notlimited to, polyvinyl acetate, partially hydrolyzed polyvinyl acetate,copolymers of vinyl acetate, acrylic acid, crotonic acid, monoalkylmaleates, ternary copolymers of vinyl acetate, crotonic acid and vinylneodecanoate, ternary copolymers of vinyl acetate, crotonic acid andvinyl propionate, copolymers of methyl vinyl ether and monoalkylmaleates, copolymers of fatty acid vinyl esters and acrylic acid ormethacrylic acid, copolymers of N-vinylpyrrolidone, methacrylic acid andalkyl methacrylates, copolymers of acrylic acid and methacrylic acid oralkyl acrylates or alkyl methacrylates, polyvinyl acetals, polyvinylbutyrals, alkyl-substituted poly-N-vinylpyrrolidones, and alkyl estersof copolymers of olefins and maleic anhydride. In some embodiments, theat least one film-forming polymer is mixed with cellulose nitrate.Polish or lacquer formulations can also contain additives common incosmetics, such as plasticizers based on phthalates or camphor,colorants or pigments, perlescent agents, sedimentation retardants,sulfonamide resins, silicates, perfumes, wetting agents such as sodiumdioctylsulfosuccinate, and lanolin derivatives. Optionally, suchformulations can also include one or more agents that increase drug fluxto the nail, e.g., ungual permeation enhancers, such asoxacyclohexadecan-2-one, and keratolytic agents). Exemplary polishformulations include (1) Eudragit® RL 100, glycerol triacetate, butylacetate, ethyl acetate and ethanol and (2) ethyl acetate, isopropanoland butylmonoester of poly(methylvinyl ether/maleic acid). Lacquers andpolishes can be applied using standard applicators known in the art(e.g. a nail brush).

In some embodiments, compositions of the invention are formulated fortopical use as described in U.S. Patent Publication 2010/0317595, theentire disclosure of which is incorporated herein by reference. Forexample, the composition may be formulated as an emulsion, colloid,suspension, semi-solid, solution, dispersion, capsule, gel, lotion,cream and the like. In some embodiments, the composition is awater-in-oil emulsion, the emulsion including hydrophobic componentssuch as a pharmaceutically acceptable oil. In some embodiments, theemulsion contains at least one oil and at least one surfactant. Thehydrophobic component may be present in an effective amount, forexample, in an amount of up to about 0.01%-90% w/v but preferably fromabout 0.01-10% by w/v, 0.05%-5% w/v, 0.05%-2% w/v or 1.0%-1.5% by w/v.Examples of useful pharmaceutically acceptable oils include vegetableoils, animal oils, mineral oils, synthetic oils and the like andmixtures thereof. In alternate embodiments, the hydrophobic componentmay comprise or consist of one or higher fatty acid glycerides. In someembodiments, the hydrophobic component comprises or consists of castoroil.

Surfactants may also be present in amounts of up to about 0.01-10% byw/v, 0.05%-5% w/v, 0.05%-2% w/v or 1.0%-1.5% by w/v. Surfactants mayinclude alcohols including carboxylated and ethoxylated alcohols, amineoxides, block polymers, fatty acids including carboxylic fatty acids,ethoxylated alkyl phenols, ethoxylated fatty esters, glycerol esters,lanolin-based derivatives, lignin derivatives, methyl esters, mono- andtri-glycerides, polyethylene glycols, polymeric surfactants,propoxylated and ethoxylated fatty acids, alcohols, or alkyl phenols,protein based surfactants, sucrose and glucose esters and derivatives.In preferred embodiments, the surfactant is a polysorbate and inparticular polysorbate 80 but other surfactants may be used.

Any known pharmaceutically acceptable surfactants may be used, includingnonionic, anionic, cationic, and combinations thereof. Nonionicsurfactants are preferred, and especially those surfactants having ahydrophile/lipophile balance (HLB) of 10 or more. Alternatively, certaincombinations of high- and low-HLB surfactants may be utilized;preferably, such mixed surfactants are used in ratio such that theaggregate surfactant HLB (when weighted according to proportions used)remains in excess of 10.

Examples of specific surfactants which may be used include, withoutlimitation, polyoxyethylene castor oil derivatives, such aspolyoxyethylene glycerol triricinoleate polyoxyl 35 castor oil(CREMOPHOR® EL, available from BASF Corporation), and polyoxyl 40hydrogenated castor oil (CREMOPHOR® RH40, available from BASFCorporation); mono-fatty acid esters of poloxyethylene (20) sorbitan,such as polyoxyethylene (20) sorbitan monooleate (TWEEN® 80),polyoxyethylene (20) sorbitan monostearate (TWEEN® 60), polyoxyethylene(20) sorbitan monopalmitate (TWEEN® 40), and polyoxyethylene (20)sorbitan monolaurate (TWEEN® 20) (all available from ICI Surfactants,Wilmington, Del.); polyoxyethylene glycol 200 monostearate (MYRJ® 52,available from Calgene Chemicals, Skokie, Ill.); polyglycerol esterswith a HLB of 10 or greater, such as decablyceryl mono- and dioleate andthe like; and mixtures thereof.

In some instances (as when the compositions are prepared assemi-solids), it may be advantageous to use at least one additionallow-HLB surfactant along with one or more of the above high-HLBsurfactant. Examples of low-HLB auxiliary surfactants which may be usedinclude, but are not limited to, polyglycerol oleates (such as CAPROL®10G40); lecithins; glyceryl monooleate or monolinoleate mixtures (suchas MYVEROL® 18-99 or 18-92); propylene glycol laurate; and sorbitanoleates such as sorbitan monooleate (SPAN® 80), sorbitan trioleate(SPAN® 85), and sorbitan sesquioleate (SPAN® 20) (all available from ICISurfactants, Wilmington, Del.). The surfactant phase may comprise about10% to 90% by weight of the composition. Preferably the surfactantcomprises about 20% to about 70% of the composition, and more preferablyabout 40% to about 60%, by weight.

It may be desirable for compositions of the invention to have highviscosity to prevent spreading of a composition from one area of thebody to other areas of the body. Accordingly, formulations may includecomponents that increase viscosity, e.g., by including thickening agentssuch as polymers or salts. Exemplary thickening agents include, but arenot limited to, polyethylene glycol, carbomer, AMMONYX® polymers,AMPHOSOL® polymers, NINOL® polymers, COCOAMIDOPROPYLAMINE OXIDE,LAURAMIDOPROPYLAMINE/MYRISTAMIDOPROPYLAMOXIDE, BIO-SOFT® 9966 TANIONIC/NONIONIC BLEND, BIO-TERGE® AS-40 CG-P SODIUM C14-16 OLEFINSULFONATE, STEPAN-MILD® L3 LAURYL LACTYL LACTATE, STEPAN® 745 GCPEG/PPG-6/2 Glyceryl Cocoate, and STEPAN® SLL-FB Sodium LauroylLactylate.

In some embodiments, compositions of the invention are formulated fortopical administration to areas of skin such as arms, legs, torso, andface. Exemplary formulations for topical administration to areas of skininclude a formulation comprising tegacid, spermaceti, methylparaben,propylene glycol, and polysorbate 80, a formulation comprising whitepetrolatum and wool fat, a formulation comprising light liquidpetrolatum and wool fat, a formulation comprising N-methyl purrolidoneand propylene glycol, and a formulation comprising alcohol,dichlorodifluoromethane, and dichlorotetrafluoroethane.

In some embodiments, compositions of the invention are formulated fortopical use as described in U.S. Patent Publication 20130150423, theentire disclosure of which is incorporated herein by reference. In thispublication, certain topical formulation are described, including atleast one water-insoluble, pharmacologically approved, alkyl celluloseor hydroxyalkyl cellulose, and the like. Alkyl cellulose or hydroxyalkylcellulose polymers for use in topical formulations are described toinclude ethyl cellulose, propyl cellulose, butyl cellulose, celluloseacetate, hydroxypropyl cellulose, hydroxybutyl cellulose, andethylhydroxyethyl cellulose, alone or in combination. In addition, aplasticizer or a cross linking agent may be used to modify the polymer'scharacteristics. For example, esters such as dibutyl or diethylphthalate, amides such as diethyldiphenyl urea, vegetable oils, fattyacids and alcohols such as acid oleic and myristyl may be used incombination with the cellulose derivative. In certain embodimentsdescribed, the topical formulation may further include hydrocarbons suchas liquid paraffin, vaseline, solid paraffin, microcrystalline wax,etc.; higher aliphatic alcohols such as cetyl alcohol, hexadecyl,alcohol, stearyl alcohol, oleyl alcohol, etc.; esters of higher fattyacids with higher alcohols such as beeswax, etc.; esters of higher fattyacids with lower alcohols such as isopropyl myristate, isopropylpalmitate, etc.; vegetable oils, modified vegetable oils, hydrouslanolin and its derivative, squalene, squalane; higher fatty acids suchas palmitic acid, stearic acid, etc. and the like. In certainembodiments described, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc. In certain embodiments described, the topical formulation mayinclude a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl-cellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and thelike. In certain embodiments described, the topical formulationdescribed is an aqueous based topical formulation. Some examples ofpatents disclosing pharmaceutical compositions which rely upon anaqueous gel composition as a vehicle for the application of a drug areU.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and5,318,780, the entire disclosures of which are herein incorporated byreference.

Formulations suitable for pulmonary administration may comprise dryparticles. Such compositions are conveniently in the form of dry powdersfor administration using a device comprising a dry powder reservoir towhich a stream of propellant can be directed to disperse the powderand/or using a self-propelling solvent/powder dispensing container suchas a device comprising the active ingredient dissolved and/or suspendedin a low-boiling propellant in a sealed container. Dry powdercompositions may include a solid fine powder diluent such as sugar andare conveniently provided in a unit dose form. Formulations forpulmonary delivery may provide the active ingredient in the form ofdroplets of a solution and/or suspension. Such formulations can beprepared, packaged, and/or sold as aqueous and/or dilute solutionsand/or suspensions, optionally sterile, comprising the activeingredient, and may conveniently be administered using any nebulizationand/or atomization device. Such formulations may be delivered by themouth or the nose.

Formulations can be for buccal administration. Such formulations may,for example, be in the form of tablets, and/or lozenges made usingconventional methods, and may contain, for example, active ingredienttogether with an orally dissolvable and/or degradable composition.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient.

Formulations for rectal delivery include, for example, suppositories,which typically are a combination of the active compound with asuppository base. Suitable suppository bases are, for example, naturalor synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols,or higher alkanols. In addition, it is also possible to use gelatinrectal capsules which consist of a combination of the active compoundswith a base. Possible base materials include for example liquidtriglycerides, polyethylene glycols, or paraffin hydrocarbons.

Oral formulations can be liquids or solids. Solid dosage forms includecapsules, tablets, pills, powders, and granules. In such solid dosageforms, the active ingredient is mixed with at least one inert,pharmaceutically acceptable excipient or carrier and/or (a) fillers orextenders, (b) binders, (c) humectants, (d) disintegrating agents, (e)solution retarding agents such as paraffin, (f) absorption acceleratorssuch as quaternary ammonium compounds, (g) wetting agents, (h), and (i)lubricants. In the case of capsules, tablets, and pills, the dosage formmay include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings and other coatings well known in the artof pharmacology. They may optionally comprise opacifying agents and canbe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner.

The topical formulation may further include one or more preservatives,stabilizers, or anti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, complexing agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other adjuvants that may be included in the drug formulation includecarriers, tackifiers, pigments, dyes, and other additives that do notadversely affect the mechanical or adhesive properties of theformulation.

The preferred dosage regimen will generally involve regular, such asone, two, three or more times a day, every other day, every three days,weekly, in each case for a period of treatment of at least one month, atleast three months, at least six months, or at least one year. Thedosage regimen can be determined by one of skill in the art and may varyaccording to factors such as the disease state, age, sex, and weight ofthe subject.

As mentioned, without wishing to be bound by any theory of theinvention, it is believed that supplying very low plasma levels of theprostaglandin F_(2α) analog produce the desired result. The dosages andplasma levels can be the same as those found useful for the treatment ofglaucoma with such analogs.

For example, tafluprost is a prostaglandin F2α analogue administered totreat glaucoma. The chemical name for tafluprost is 1 methylethyl(5Z)-7-{(1R, 2R, 3R,5S)-2-[1E)-3,3-difluoro-4-phenoxy-1-butenyl}-3,5-dihydroxycyclopentyl]5-heptenoate.It is supplied as a solution at 0.0015% (15-μg/mL) (Zioptan™, Merck).The dose is an eye drop once daily in an affected eye, with 0.3-mL(4.5-μg) tafluprost in the evening. Following instillation of one dropof the 0.0015% solution once daily into each eye of healthy volunteers,the plasma concentrations of tafluprost acid peaked at a median time of10 minutes on both Days 1 and 8. The mean plasma C_(max) of tafluprostacid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. Themean plasma AUC estimates of tafluprost acid were 394 pg min/mL and 432pg min/mL on Day 1 and 8, respectively.

Latanoprost is a prostaglandin F2a analogue administered to treatglaucoma. Its chemical name isisopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.Latanoprost ophthalmic solution is supplied as a sterile, isotonic,buffered aqueous solution containing 50 micrograms of latanoprost perml. The recommended dosage is one drop (1.5 μg) in the eye(s) once dailyin the evening. The distribution volume in humans is 0.16±0.02 L/kg. Theacid of latanoprost can be measured in aqueous humor during the first 4hours, and in plasma only during the first hour after localadministration.

Bimatoprost 0.01% and 0.03% ophthalmic solution is a syntheticprostamide analog administered to treat glaucoma. Its chemical name is(Z)-7-[(1R,2R,3R,5S)-3,5Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide.One drop of bimatoprost ophthalmic solution 0.03% administered oncedaily to both eyes of 15 healthy subjects for two weeks, resulted inblood concentrations that peaked within 10 minutes after dosing and werebelow the lower limit of detection (0.025 ng/mL) in most subjects within1.5 hours after dosing. Mean C_(max) and AUC0-24 hr values were similaron days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng hr/mL,respectively, indicating that steady state was reached during the firstweek of ocular dosing. Bimatoprost is moderately distributed into bodytissues with a steady-state volume of distribution of 0.67 L/kg. Inhuman blood, bimatoprost resides mainly in the plasma.

Travoprost is a prostaglandin F_(1α) analog administered to treatglaucoma. Its chemical name is[1R-[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester.Following absorption into the eye, the free acid form of travoprostinteracts with the endogenous FP prostanoid receptor to enhance aqueoushumor outflow and lower intraocular pressure (IOP). Travoprost issupplied as a 0.004% ophthalmic solution. The recommended dosage is onedrop in the eye(s) once daily in the evening. Plasma concentrations ofthe free acid administered daily as a single drop in both eyes are below0.01 ng/ml (the quantitation limit of the assay) in two-thirds of thesubjects. In those individuals with quantifiable plasma concentrations(N=38), the mean plasma C_(max) was 0.018±0.007 ng/ml (ranged 0.01 to0.052 ng/mL) and was reached within 30 minutes.

The foregoing preparations of tafluprost, latanoprost, bimatoprost andtravoprost may be administered to the eye in the above described dailydoses to prevent or therapeutically treat migraine, as demonstrated inthe examples. The preparations may be applied to one eye or both eyes.These solutions also may be administered to other epithelial tissues toachieve the same effects. For example, a single daily drop of suchsolutions to the base of the finger nail and adjoining skin (e.g., onone, two, three, four or five fingers of one hand or both hands) andpermitting the solution to dry yields effective concentrations forpreventing and/or therapeutically treating migraine. In some embodimentsof any one of the preparations, the preparation may be applied to theeye or the nail area daily for at least one month (e.g., for one month,two months, three months, four months, five months, six months, orlonger).

In some embodiments, compositions of the invention may include more thanone therapeutic agent, e.g., a prostaglandin F_(2α) analog and at leastone additional therapeutic agent that is not a prostaglandin F_(2α)analog which treats migraine (therapeutically or prophylactically). Insome embodiments, the composition comprises a prostaglandin F_(2α)analog or pharmaceutically acceptable salt thereof, or a derivativethereof, formulated together with a drug which (i) is not aprostaglandin F_(2α) analog or pharmaceutically acceptable salt thereof,or a derivative thereof, and (ii) that is a drug which treats migraine.

In some embodiments, methods of the invention may include the use of aprostaglandin F_(2α) analog and at least one additional therapy whichtreats migraine (therapeutically or prophylactically), such as atherapeutic agent (e.g., a drug which treats migraine), a laser therapy,surgery, a device and/or a behavioral therapy.

Drugs which are known to treat migraine include therapeutic (abortive)and prophylactic drugs. Abortive treatments include the triptans, whichspecifically target serotonin. Examples include Almotriptan (AXERT®),Eletriptan (RELPAX®), Frovatriptan (FROVA®), Naratriptan (AMERGE®,NARAMIG®), Rizatriptan (MAXALT®), Sumatriptan (ALSUMA®, DosePro®,IMITREX®, SUMAVEL®, TREXIMET®, ZECUITY®), and Zolmitriptan (ZOMIG®).Other abortive migraine drugs areacetaminophen-isometheptene-dichloralphenazone (MIDRIN®),Dihydroergotamine (D.H.E. 45 Injection, Migranal Nasal Spray), andErgotamine tartrate (Cafergot). In addition, over-the-countermedications such as Advil® Migraine (containing ibuprofen), Excedrin®Migraine (containing aspirin, acetaminophen, caffeine), and Motrin®Migraine Pain (containing ibuprofen) are known. Diclofenac is anothernon-steroidal anti-inflammatory drug (“NSAID”), known chemically as[(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid, known to treatmigraine. The following drugs are mainly used for nausea related tomigraine headaches in addition to migraine treatment: Metoclopramide(REGLAN®), Prochlorperazine (COMPAZINE®) and Promethazine (PHENERGAN®).Some drugs are used for headache pain but are not specific formigraines. These include analgesics, narcotics, and barbiturates. Sincethey can be habit forming, they have drawbacks relative to non-additivecompounds. Drugs used to prevent migraine include medications to treathigh blood pressure: beta-blockers (propranolol (INDERAL®), timolol),calcium channel blockers (verapamil (COVERA®)); Antidepressants:amitriptyline (ELAVIL®), nortriptyline (PAMELOR®); Antiseizuremedications: gabapentin (NEURONTIN®), topiramate (TOPAMAX®), valproicacid (Depakote®); and Botulinum toxin (BOTOX®).

Other exemplary additional therapies which treat migraine(therapeutically or prophylactically), include relaxation training,thermal biofeedback, electromyography biofeedback, cognitive-behavioraltherapy, arterial surgery, trigger site release surgery, patent foramenovale closure surgery, spinal cord stimulation, biofeedback stimulatordevices, neurostimulator devices (e.g., a transcutaneous electricalnerve stimulation device), vestibular rehabilitation exercise, occipitalnerve stimulation, acupuncture, and infrared laser therapy.

In some embodiments, the subject is not affected by or does not exhibitsymptoms of and one or more of, any combination of, or all of: glaucoma,ocular hypertension, blepharospasm, eyelash hypotrichosis, Meniere'sdisease, tinnitus, hearing loss or a hair-thinning or baldness condition(e.g., alopecia or male-pattern baldness). In some embodiments, thesubject is not being treated to prevent sunburn. In some embodiments,the subject is not being treated to improve nail health. In someembodiments, the subject is not in need of or being treated for any oneor any combination of a reduction of body fat or is not affected by orexhibit symptoms of one or more of: Cushing syndrome, pseudo-Cushingsyndrome, drug-induced obesity, HIV-related lipodystrophy,hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity,polycystic ovarian disease, depression, binge eating, Prader-Willisyndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turnersyndrome, growth hormone deficiency, growth hormone resistance, and/orleptin deficiency or resistance.

EXAMPLES Example 1

A 53 year old male subject was treated with ocular administration oftravoprost 0.0004% once per day as a single drop in both eyes in theevening. The subject reported that he had no migraines after being ontherapy for 30 days.

Example 2

A 63 year old male in good health with a history of migraine headaches(1-3 per week) directly related to classic triggers (cheese, red wine,alcohol, monosodium glutamate, shrimp, mushrooms, and lack of sleep)daily administered 1 drop (approximately 0.05 ml) of the prostaglandin,LUMIGAN® (bimatoprost ophthalmic solution), topically to the cuticleregion of four finger nails on one hand. After 1 month, the frequency ofheadaches decreased from the typical pattern of 1-3 per week to blocksof time extending 2-3 weeks without any headaches.

After three months of daily topical administration of LUMIGAN®,treatment was discontinued. In the two months post treatment thefrequency of migraine headaches returned to the pre-treatment level (1-3per week).

LUMIGAN® treatment was then restarted with daily topical administrationto four finger nails for four months. A similar decrease in frequency inheadaches was observed after 1 month as noted with first treatmentabove. Upon cessation of treatment, the frequency of headaches returnedto baseline levels (1-3 per week) after one month.

LUMIGAN® treatment was initiated again on four finger nails for twomonths with a similar decrease in frequency of headaches within onemonth, as noted with LUMIGAN® use previously.

For the next three months the administration was tapered to three fingernails without any loss of the therapeutic effect.

The dose was tapered further to two finger nails for one month with nochange in headache frequency again. Treatment was stopped.

Within one month of cessation of LUMIGAN® treatment, migraine headacheoccurrence returned to baseline frequency.

Treatment then was restarted two months later with topicaladministration to three finger nails. A decrease with headache frequencywas observed within the first two weeks post reinitiating treatment.

After two months the dose was reduced to topical administration to twofinger nails for three months without return to the baseline headachefrequency.

After three months the dose was tapered to daily topical administrationto one finger nail. The migraine headache frequency returned to thepre-treatment baseline level (1-3 per week) within two weeks of the dosereduction.

After one month with administration to one finger nail only, the dosewas increased to daily administration to two finger nails. Headachefrequency was reduced within two weeks.

Dosage was maintained at two finger nails daily for another two monthswith continued reduction in headache frequency.

Example 3

A 32 year old female, with a history of experiencing migraine headachesdaily, started treatment by administering a single drop of LUMIGAN® toeach of four finger nails on one hand. The drops were maintained on thenail beds for five minutes. Within a couple of weeks, she rarely had aheadache, and when she had the occasional headache, it was mild incomparison to pretreatment.

After ceasing treatment, the daily headaches returned.

Example 4

A 58 year old female, with a history of migraine headaches for fortyyears, had been seen by multiple headache specialists and had avoidedall food triggers without reduction in headache frequency or intensity.After about 45 days of once-daily administration of a single LUMIGAN®drop to each of four finger nails on one hand, her headache frequencyand severity decreased.

After ceasing treatment, the frequency and severity of headachesreturned to pretreatment levels.

Example 5

A 54 year old male with a fifteen year history of severe migraineheadaches refractory to multiple therapies, started treatment withTRAVATAN Z® (travoprost ophthalmic solution) administered topically toone eye daily. One month later the migraine headaches had totallyresolved.

Example 6

A 64 year old female with a history of migraine headaches (one per week)was started on daily topical administration of the prostaglandin,XALATAN® (latanoprost ophthalmic solution), to both eyes daily. Aftersix months of treatment, the frequency of migraine headaches was reducedto one per 6 months and the severity was much milder.

Example 7

A 47 year old male with a history of weekly migraine headaches startedapplying one drop of LUMIGAN® to each of three finger nails on one hand.After two weeks, the frequency and severity of the migraine headachesdecreased and was maintained for three months of treatment.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present invention toits fullest extent. The specific embodiments are, therefore, to beconstrued as merely illustrative, and not limitative of the remainder ofthe disclosure in any way whatsoever. All publications cited herein areincorporated by reference for the purposes or subject matter referencedherein.

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

What is claimed is:
 1. A method of treating migraine in a subject inneed thereof, the method comprising oral or mucosal membraneadministration of a composition comprising latanoprost, isopropylunoprostone, bimatoprost, travoprost, or tafluprost, or apharmaceutically acceptable salt thereof, to the subject, in an amounteffective to treat migraine; provided that the mucosal membrane is notan eye.
 2. The method of claim 1, wherein the administration to thesubject reduces the frequency of migraines in the subject.
 3. The methodof claim 1, wherein the administration to the subject is therapeutic. 4.The method of claim 1, wherein the administration to the subject is oraladministration.
 5. The method of claim 1, wherein the administration tothe subject is administration to a mucous membrane.
 6. The method ofclaim 5, wherein the mucous membrane is of the rectum, nose, throat,lungs, or buccal cavity.
 7. The method of claim 5, wherein theadministration is sublingual, suppository, or inhaled delivery.
 8. Themethod of claim 1, wherein the composition comprises bimatoprost,travoprost, or latanoprost, or a pharmaceutically acceptable saltthereof.
 9. The method of claim 1, wherein the composition comprisesbimatoprost, or a pharmaceutically acceptable salt thereof.
 10. A methodof treating migraine in a subject in need thereof, the method comprisingsustained release administration of a composition comprisinglatanoprost, isopropyl unoprostone, bimatoprost, travoprost, ortafluprost, or a pharmaceutically acceptable salt thereof, to thesubject, in an amount effective to treat migraine.
 11. The method ofclaim 10, wherein the administration to the subject reduces thefrequency of migraines in the subject.
 12. The method of claim 10,wherein the administration to the subject is therapeutic.
 13. The methodof claim 10, wherein the sustained release administration to the subjectis oral administration.
 14. The method of claim 10, wherein thesustained release administration to the subject is topicaladministration.
 15. The method of claim 14, wherein the topicaladministration comprises delivery of the composition by a transdermaldelivery system.
 16. The method of claim 15, wherein the transdermaldelivery system is a drug-containing device which releases one or moredrugs at a predetermined rate.
 17. The method of claim 10, wherein thecomposition comprises bimatoprost, travoprost, or latanoprost, or apharmaceutically acceptable salt thereof.
 18. The method of claim 10,wherein the composition comprises bimatoprost, or a pharmaceuticallyacceptable salt thereof.
 19. A method of treating migraine in a subjectin need thereof, the method comprising administering, to the eye of thesubject, a composition comprising isopropyl unoprostone, bimatoprost,travoprost, or tafluprost, or a pharmaceutically acceptable saltthereof, in an amount effective to treat migraine.
 20. The method ofclaim 19, wherein the administration to the subject is reduces thefrequency of migraines in the subject.
 21. The method of claim 19,wherein the administration to the subject is therapeutic.
 22. The methodof claim 19, wherein the composition comprises bimatoprost ortravoprost, or a pharmaceutically acceptable salt thereof.
 23. Themethod of claim 19, wherein the composition comprises bimatoprost, or apharmaceutically acceptable salt thereof.